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Decorin causes autophagy in endothelial cells via Peg3

Author:
Buraschi, Simone, Neill, Thomas, Goyal, Atul, Poluzzi, Chiara, Smythies, James, Owens, Rick T., Schaefer, Liliana, Torres, Annabel, Iozzo, Renato V.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.28 pp. E2582
ISSN:
0027-8424
Subject:
angiogenesis, autophagy, endothelial cells, gene expression, membrane potential, mitochondrial membrane, proteoglycans, tumor suppressor genes, vascular endothelial growth factor receptor-2, vascular endothelial growth factors
Abstract:
Soluble decorin affects the biology of several receptor tyrosine kinases by triggering receptor internalization and degradation. We found that decorin induced paternally expressed gene 3 (Peg3), an imprinted tumor suppressor gene, and that Peg3 relocated into autophagosomes labeled by Beclin 1 and microtubule-associated light chain 3. Decorin evoked Peg3-dependent autophagy in both microvascular and macrovascular endothelial cells leading to suppression of angiogenesis. Peg3 coimmunoprecipitated with Beclin 1 and LC3 and was required for maintaining basal levels of Beclin 1. Decorin, via Peg3, induced transcription of Beclin 1 and microtubule-associated protein 1 light chain 3 alpha genes, thereby leading to a protracted autophagic program. Mechanistically, decorin interacted with VEGF receptor 2 (VEGFR2) in a region overlapping with its natural ligand VEGFA, and VEGFR2 was required for decorin-evoked Beclin 1 and microtubule-associated protein 1 light chain 3 alpha expression as well as for Peg3 induction in endothelial cells. Moreover, decorin induced VEGFR2-dependent mitochondrial fragmentation and loss of mitochondrial membrane potential. Thus, we have unveiled a mechanism for a secreted proteoglycan in inducing Peg3, a master regulator of macroautophagy in endothelial cells.
Agid:
1737320